Flavonoid‐Derived Human Phenyl‐γ‐Valerolactone Metabolites Selectively Detoxify Amyloid‐β Oligomers and Prevent Memory Impairment in a Mouse Model of Alzheimer's Disease

Scope Amyloid‐β oligomers (AβO) are causally related to Alzheimer's disease (AD). Dietary natural compounds, especially flavonoids and flavan‐3‐ols, hold great promise as potential AD‐preventive agents but their host and gut microbiota metabolism complicates identification of the most relevant...

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Bibliographic Details
Published in:Molecular nutrition & food research 2020-03, Vol.64 (5), p.e1900890-n/a
Main Authors: Ruotolo, Roberta, Minato, Ilaria, La Vitola, Pietro, Artioli, Luisa, Curti, Claudio, Franceschi, Valentina, Brindani, Nicoletta, Amidani, Davide, Colombo, Laura, Salmona, Mario, Forloni, Gianluigi, Donofrio, Gaetano, Balducci, Claudia, Del Rio, Daniele, Ottonello, Simone
Format: Article
Language:English
Subjects:
Alzheimer Disease - etiology
Alzheimer Disease - prevention & control
Alzheimer's disease
Alzheimer's disease prevention
Amyloid
Amyloid beta-Peptides - genetics
Amyloid beta-Peptides - metabolism
Amyloid beta-Peptides - toxicity
amyloid oligomer detoxification
Animals
Atomic force microscopy
Biocompatibility
Biomarkers
Cytotoxicity
Diet
Dietary intake
Disease Models, Animal
flavan 3‐ol flavonoids
Flavonoids
Flavonoids - chemistry
Food intake
HEK293 Cells
Humans
Impairment
Inflammation
Intestinal microflora
Lactones - metabolism
Lactones - pharmacology
Male
Mammalian cells
Memory Disorders - prevention & control
Metabolism
Metabolites
Mice, Inbred C57BL
Microbiota
Mode of action
Neurodegenerative diseases
Oligomers
Peptide Fragments - metabolism
phenyl‐γ‐valerolactones
Polypeptides
polyphenols
Toxicants
Toxicity
Yeasts
Yeasts - drug effects
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Summary:Scope Amyloid‐β oligomers (AβO) are causally related to Alzheimer's disease (AD). Dietary natural compounds, especially flavonoids and flavan‐3‐ols, hold great promise as potential AD‐preventive agents but their host and gut microbiota metabolism complicates identification of the most relevant bioactive species. This study aims to investigate the ability of a comprehensive set of phenyl‐γ‐valerolactones (PVL), the main circulating metabolites of flavan‐3‐ols and related dietary compounds in humans, to prevent AβO‐mediated toxicity. Methods and results The anti‐AβO activity of PVLs is examined in different cell model systems using a highly toxic β‐oligomer‐forming polypeptide (β23) as target toxicant. Multiple PVLs, and particularly the monohydroxylated 5‐(4′‐hydroxyphenyl)‐γ‐valerolactone metabolite [(4′‐OH)‐PVL], relieve β‐oligomer‐induced cytotoxicity in yeast and mammalian cells. As revealed by atomic force microscopy (AFM) and other in vitro assays, (4′‐OH)‐PVL interferes with AβO (but not fibril) assembly and actively remodels preformed AβOs into nontoxic amorphous aggregates. In keeping with the latter mode of action, treatment of AβOs with (4′‐OH)‐PVL prior to brain injection strongly reduces memory deterioration as well as neuroinflammation in a mouse model of AβO‐induced memory impairment. Conclusion PVLs, which have been validated as biomarkers of the dietary intake of flavan‐3‐ols, lend themselves as novel AβO‐selective, candidate AD‐preventing compounds. Circulating phenyl‐valerolactone‐based metabolites, derived from cocoa and other flavan‐3‐ol‐rich foods through combined, microbial and human cell‐mediated bioconversion, selectively detoxify amyloid‐β oligomers, the most proximal causative agents of Alzheimer's disease.
ISSN:1613-4125
1613-4133
DOI:10.1002/mnfr.201900890